The expression level of the EGFR protein was inversely related to that of neurofibromin in all the cells tested, suggesting that neurofibromin deficiency may cause upregulated EGFR in the NF1-associated MPNSTs. The antiapoptotic Bcl-xL protein upregulated in the MPNST cells caused an increase in resistance to anticancer drugs in MPNST cells. Finally, the Ras/Erk/Sp1-signaling pathway mediated the elevated transcriptional expression of EGFR and Bcl-xL in MPNST cells.
Meanwhile, Bcl-xL unexpectedly modulated the neurofibromin levels in the opposite direction. The knockdown of Bcl-xL caused an increase in the neurofibromin level, whereas Bcl-xL overexpression resulted in a decreased neurofibromin level. Further experimentation demonstrated that Bcl-xL regulates the neurofibromin level by modulating the ubiquitin-mediated proteolysis of neurofibromin. These results suggest that Bcl-xL plays a crucial role in the regulation of EGFR-mediated Ras signaling in a positive feedback manner by modulating cellular neurofibromin levels.
The combined treatment option of the EGFR inhibitor Erlotinib, the Bcl-xL inhibitor ABT-737, and apoptosis inducer Doxorubicin could effectively induce synergistic cytotoxicity in MPNST cells with minimal side effects. These results suggest that pharmacological inhibitions of EGFR and Bcl-xL in combination with anticancer drug inducing apoptosis may be a potential therapeutic strategy for the treatment of NF1-associated MPNSTs.
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